Iodomethylate compounds of the



Patented June 9, 1 953 IODOMETHYLATE COMPOUNDS or run DIMETHYL. XANTHINESERIES,

7 Alexis J. M. Moussalli, Andr Soubiran, and

Pierre Chabrier, Paris, France No Drawing. Application June l3, 1949,Serial No. 98,872. In France-June 28, 1948 2 Claims. (01. 260253) KTheophylline or 1:3-dimethyl xanthine as employed for therapeuticpurposes issparingly soluble in water, and it has been endeavoured toconvert it into more readily soluble derivatives, particularly bysubstituting suitable radicles for the hydrogen atom bound to thenitrogen atom in 7-position. Thus it has been proposed to substitute aglyceryl radicle. However the compounds or molecule associationsheretofore proposed to allow of a more practically administration oftheophylline show the inconveniency of exhibiting an alkalinity whichalways renders such an administration painful. A compound closelyrelated with theop-hylline from the standr it should be "appreciatedthat we do not restrict point of molecular structure is theobromine or 3'7-dimethyl-xanthine andsimilar difliculties are experienced in thepractical employment thereof. It is an object of our invention toprovide a new class of dimethyl x'anthine derivativeswhich are free fromthe above drawback and allow of efiecting a substantially painlessadministration of theophylline or theobromine through parenteral way,particularly as aqueous solutions thereof by reason of the greatsolubility of said derivatives in water.' I

A further object is to provide dimethyl xan-thine derivatives which arecapable of associating the action'of either theophylline or theobrominewith that of other medicines under desirable conditions of synergy.

According to this invention we provide new derivatives of theophylline'and theobromine wherein an organic "radical having a primary, secondaryor tertiary? (possibly salified) amino group or a quaternary group issubstituted for the hydrogen atom connected to the nitrogen atom inposition '7 or 1.

Although any organic radical may be present,

we prefer for obvious economical reasons, simple radicals derived fromcompounds which are readi-Y.

made thereto for illustrating our invention, but

ourselves to fixing amino-alkyl radicals, par-'- ticularlyza-amino-alkyl radicals, nor to selecting radicals 'which'bear tertiaryamino groups.

7-(B-diethylamino-ethyl) theophylline has the advantages of being easilyproduced by condensingtheophylline with B-diethylamino ethyl chloride inalkaline medium, and of being very soluble in water; furthermore iteasily lends' itself to the production of mineral and organic acid saltsas well as quaternary compounds. Among the products thus obtainable,there is a large number of substances which readily dissolve-in waterand have a neutral reaction, so that painless.administrations thereofthrough parenter'alway'are possible. The same is true withp-dime'thylamino ethyl theophylline and cor responding derivatives oftheobromine.

I Insteadof dialkylamino alkane halide, we may I also cause dimethylxanthine to react with. the hydro-chloride of'said halide; it is onlynecessary to add the required proportion of alkali for neutralizingall'hydro'chloric acid produced, to the medium in which the reactiontakes place.

, I nstead of condensing dimethyl xanthine (theophylline or theobromine)directly with adialkyb amino alkyl halide, we may also reactan alka'nolhalide with dimethyl -xanthine to produce-the 7 or 1 hydroxy-alkylderivative of dimethyl 'xanthine, then substitute a halogen atom for thehydroxy group for example by means of thinoyl chloride, and finallyreact a dialkylamine with said halogeno derivative, eventually to obtainthe dialkylamino derivative of dimethyl Xanthine. Thus glycolmonochlorhydrin and. theophylline in substantially equimolar proportionsmay be reacted in an alkaline medium, then the product-may be treatedwith thionyl chloride in the molar proportion of 1:2 between said prod-Example 1 One mol of theophylline was dissolved in a 1 per cent aqueoussolution of one mol ofrcaustic soda. One mol of ,B-diethylamino ethylchloride was added, and the'mixture was boiled for 6 hours with reflux,while stirring. The product was evaporated to dryness in a vacuo, andthe dry pasty residue was taken up in acetone, to separate the desiredcompound from sodium chloride associated therewith. The acetone solutionwas distilled to remove solvent therefrom and 1 :3-dimethy1-7-(fi-diethylaminm-ethyl xanthine.

was obtained as a white mass which has a melting point of about 74 C.and is very soluble in water, alcohol and acetone.

By oxidizing the compound in an aqueous solu' tion by means of chlorinewater, bromine water or nitric acid, we obtained after evaporating thesolution on a water-bath, a yellow residue mainly constituting of amalicacid which 'is' given an orange red colour by ammonia vapours (a reaction which is common to theophylline, theobromine and cafeine).

By operating exactly in the same manner from theobromine instead oftheophylline, we obtained 3 :7 -dimethyl-le-diethylamino) ethyl-xanthinewhich has a melting point of 60 C... 7

Example 2 We neutralised 1:3-dimethyl-7 (e diethylamino) ethy1 xanthinedissolved in a, solvent therefor, for example water or alcohol, by meansof the calculated amount of a mineral or organic acid, or we efiected adouble decomposition with a salt of such an acid; we thus obtained asalt of said xanthine compound.

Thus the following compounds were prepared:

- Melting point, C. Hyrochloride 240 Hydroiodicle I 198Camphorsulphonate' 174 Picrate 210 Dehydrocholate 225 P-amino-benzoate p215 Neutralsuccinatepxmni 197 Example 3 'To an alcohol oracetone-solution of 1:3-di-' methyl-7e (fi-diethylamino) -ethy1xanthine; we

added 1 mol of methyl iodide and-we allowed to react; th iodo-methylateof said xanthine compound'precipitated'with a yield above 90 per cent.The iodo-methylate has a melting point of 234 C. and is soluble in waterbut little soluble in organic solvents.

g 7 Example 4 We worked in the same conditions as stated in Example 1,but e-dimethylamino-ethyl chloride.

was substtiuted for B-diethylamino-ethyl chloride; we thus obtained1:3-dimethyl-7-(fi-dimethylamino) -ethyl xanthine HzC-CHz-N which has amelting point of 95 (3.; the hydrochloride thereof has a melting pointof 260 C.

In operating as disclosed in Examples 2 and 3, salts and quaternaryammonium derivatives were easily produced from the above dimethylaminoethyl xanthine compound.

4 Example 5 which is soluble in water.

' Example 6 We dissolved 20 parts by weight of '7-(p-diethylamino)-ethyltheophylline in 60 parts by weight of acetone, and we added 15 parts byweight of methyl camphosulphonate to the acetone solution. After 12hours of contact, the 7-( 3diethylamino)-ethyl theophyllinemethocamphosulphonate was filtered off; the compound.

melts at 193 C. and is very solublein water; it has the formula: I

Example 7 One mol of theophylline was dissolved in a 2 per cent aqueoussolution of two mols of caustic soda, and one mol of hydrochloride of,8- morpholyl-ethyl chloride was added to the solution; the whole wasboiled with reflux while stirring, for 4 hours. It was then evaporatedto dryness, and the dry residue was taken up in acetone for separatingthe desired compound from accompanying sodium chloride. The acetonesolution was distilled to remove solvent, and 7-(fi-morpholyD-ethyltheophylline was obtained as a white powder having a melting point of 82C..

1 Example 8 We worked according to Example 7, substitut inghydrochloride of fi-piperidyl-ethyl chloride for. hydrochloridefi-morpholyl-ethyl chloride. We thus obtained 'l-(e-piperidyD-ethyltheophylline having a melting point of 132 0.; it is less soluble inwater than the morpholyl-ethyl compound and the diethylamino-ethylcompound, and can be purified by recrystallisation out of boiling water.It has the following formula:

Example 9 We Worked according to Example 3 with 1-(5- diethylamino)-ethyl theobromine instead of 7-(5-diethylamino)-ethyl theophylline; wethus obtained l-(B-diethylamino)-ethyl theobromine iodomethylate havinga melting point of 192 C.

It should be understood that the foregoing examples are given solely forthe purpose of illustrating our invention, and should not be construedas limiting said invention thereto.

We claim:

1. 7 (fi-diethylamino-ethyl) 1 3 dimethylxanthine iodo-methylate, acompound which has a melting point of 234 C., is soluble in water butonly slightly soluble in organic solvents.

I 2. An iodomethylate quaternary ammonium compound of atertiary-amino-alkyl-dimethylxanthine of the general formula 6 in whichRn stands for a group selected from the class consisting of(di-lower-alkyl-amino)-lower alkyl groups,

CHZCH2 0 N-lower alkyl groups oHr-om and CHz-CH2 H2O Nlower alkyl groupsCHz CH2 ALEXIS J. M. MOUSSALLI. ANDRE: SOUBIRAN. PIERRE CHABRIER.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 1,414,333 Altwegg u May 2, 1922 2,397,799 Martin et a1 Apr. 2,1946 2,429,275 Parker Oct. 21, 1947 OTHER REFERENCES Quevauviller etal., Ann. Pharm. Franc 7 32-9 (1949).

Jensen et al., Acta Chemica Scandanavica, 2, 381-383 (1948).

Richter, Textbook of Organic Chemistry, 1938 edition, John Wiley andSons, Inc., New York, N. Y., pp. 229, 230 and240.

2. AN IODOMETHYLATE QUATERNARY AMMONIUM COMPOUND OF ATERTIARY-AMINO-ALKYL-DIMETHYLXANTHINE OF THE GENERAL FORMULA